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Leukemia Research 34 (2010) 864–870

Contents lists available at ScienceDirect

Leukemia Research

journa l homepage: www.e lsev ier .com/ locate / leukres

oes iron chelation therapy improve survival in regularly transfused lower riskDS patients? A multicenter study by the GFM

hristian Rosea, Sabine Brechignacb, Dominique Vassilief c, Laurent Pascala, Aspasia Stamatoullasd,gnes Guercie, Dalila Larbaaf, Francois Dreyfusc, Odile Beyne-Rauzyg, Marie Pierre Chauryh,ydie Royi, Stephane Cheze j, Pierre Morelk, Pierre Fenauxb,∗,FM (Groupe Francophone des Myélodysplasies)

Service d’Onco-Hématologie, Hôpital Saint Vincent de Paul, Université Catholique de Lille, Lille, FranceService d’Hématologie clinique and Paris 13 University, Hôpital Avicenne, Assistance Publique, Hôpitaux de Paris (AP-HP), 125 rue de Stalingrad, 93009, Bobigny, FranceService d’Hématologie, Hôpital Cochin, Paris, FranceService d’Hématologie, Centre H. Becquerel, Rouen, FranceService d’hématologie Hôpitaux de Brabois Nancy, Nancy, FranceEtablissement Francais du Sang, Pontoise, FranceService de Médecine Interne, CHU de Toulouse Purpan, Toulouse, FranceService d’Hématologie, CHU Dupuytren, Limoges, FranceService d’Hématologie, CHU de Poitiers, Poitiers, FranceService d’Hématologie, CHU de Caen, Caen, FranceService d’Hématologie, Centre Hospitalier Schaffner, Lens, France

r t i c l e i n f o

rticle history:eceived 22 September 2009eceived in revised form2 December 2009ccepted 12 December 2009vailable online 2 February 2010

eywords:

a b s t r a c t

Background: Iron chelation therapy (CT) improves survival in thalassemia major but its beneficial effectson survival in MDS patients remain uncertain.Methods: We analyzed, by multivariate analysis, survival and causes of deaths in 97 low or intermediate1 IPSS patients regularly transfused as outpatients, chelated or not, who were included during a monthperiod and followed for 2.5 years.Results: 44 (45%) of patients were not chelated and 53 (55%) received CT, mainly with deferoxamine, for atleast 6 months (median duration of chelation 36 months, range 6–131+). During the follow-up period, 66of the 97 patients died, including 51% and 73% of chelated and non-chelated patients, respectively. Median

ransfusionyelodysplastic syndrome

urvival

overall survival was 53 months and 124 months in non-chelated and in chelated patients (p < 0.0003).Causes of death did not significantly differ between the two groups (p = 0.51). In multivariate Cox analysis,adequate chelation was the strongest independent factor associated with better OS.Conclusion: Iron chelation therapy appears to improve survival in heavily transfused lower risk MDS, butprospective randomized studies are required to confirm our findings, and to determine more precisely

otent

. Introduction

Myelodysplastic syndromes (MDS) are clonal stem cell disordersharacterized by ineffective hematopoiesis leading to peripheralytopenias, especially anemia, and by frequent progression to acuteyeloid leukemia (AML). The French-American-British (FAB) and

ave been used to categorize MDS [1,2], while the Internationalrognostic Scoring System (IPSS), which combines cytogeneticesults, the number of cytopenias, and the percentage of marrow

∗ Corresponding author. Tel.: +33 1 48 95 70 50; fax: +33 1 48 95 70 58.E-mail address: pierre.fenaux@avc.aphp.fr (P. Fenaux).

145-2126/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.oi:10.1016/j.leukres.2009.12.004

ial survival benefit.© 2010 Elsevier Ltd. All rights reserved.

blasts, is the most widely used prognostic score [3]. Transfusiondependency is also an independent prognostic factor for survivalin MDS. Its detrimental effect on survival is correlated to theimportance of transfusion requirement and is more pronouncedin lower risk patients, and this parameter has been introduced theWHO classification in a new WHO based prognostic scoring sys-tem (WPSS) [4]. Most MDS patients are elderly and they frequentlyhave various co-morbidities, whose number increases with age andwhich have demonstrated independent prognostic value for sur-

Treatment of MDS varies according to risk group. In lower-risk patients (including IPSS low and int-1 risk groups), treatmentmainly aims at improving cytopenias, especially anemia [8]. How-ever, although several drugs may improve anemia, sometimes

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C. Rose et al. / Leukemia

urably [5,9], most of lower risk MDS eventually require red bloodell (RBC) transfusions during their disease course [10,11]. Longerm RBC transfusions lead to iron overload mainly due to anncrease in reticulo-endothelial iron recycling [12]. Most regularlyransfused MDS patients have biological signs of iron overload,articularly a high serum ferritin level [13–15], elevated serumerritin level may carry a poor prognostic impact in transfusion-ependent refractory anemia [16], although this has been recentlyisputed [17] and can adversely affect the outcome of MDS patientseceiving allogeneic stem-cell transplantation [18]. Cardiac, livernd endocrine (diabetes mellitus) dysfunction [19,20] due to ironverload and often leading to fatal outcome has been reported ineavily transfused lower risk MDS patients, especially refractorynemia with ringed sideroblasts [20] and the 5q-syndrome [19].owever, the clinical impact of iron overload on morbidity andortality is often difficult to precisely evaluate in MDS [12] due to

he frequency of confounding factors (co-morbidities, ageing, MDSvolution and MDS complications) [19–21].

Potential complications of transfusional iron overload may befficiently prevented by iron chelation therapy (CT) and a posi-ive impact of iron CT on survival has been clearly demonstratedn thalassemia major [22,23]. In MDS, benefits of iron CT on sur-ival, and sometimes on hematopoiesis, have only been suggestedn small retrospective studies [24–26]. Therefore, indications ofron chelation therapy (CT) in MDS patients are mainly based onxpert consensus [27,28] and have not been validated in large MDSohorts.

In the present study, we assessed the role of iron CT on survivaln a cohort of regularly transfused lower risk MDS from 18 centersf the Groupe Francophone des Myélodysplasies (GFM).

. Patients and methods

.1. Patients

In 2005, we included, during a month period (May 15th to June 15th, 2005)ll MDS patients who received RBC transfusions as outpatients in 18 centers of theFM, after they gave informed consent. The following data were collected for eachatient: medical history (co-morbidities, concomitant treatments), hematologicalata, transfusion history, serum ferritin level at diagnosis and during follow-up,helation therapy (type, tolerance, date of onset and termination, reasons for dis-ontinuation, compliance, and impact on transfusion dependence and hematologicalharacteristics). We reassessed this cohort 2 and a half years after inclusion at theeference date of November 15th 2007 (end of follow up) with reanalysis of theransfusion requirement, chelation therapy, iron overload (serum ferritin level), pro-ression to AML, overall survival and cause of deaths. Patients with low or int 1 IPSS,ho accounted for 97 of the patients included in this cohort, are the subject of theresent work.

Co-morbidities were scored using an index adapted from Charlson’s index [29].or each patient, the number of co-morbidities was quantified and co-morbiditieslassified into two groups: a group possibly related to iron overload (including non-schemic cardiomyopathy, cardiac rhythmic disorders, liver disease, and diabetes

ellitus) and a group of a priori non-iron overload related co-morbidities (othero-morbidities).

The date of onset of RBC transfusions and the total number of RBC concen-rates administered were recorded from the blood delivery software of each center,

andatory in France since 1990, or from medical files in the rare patients transfusedefore 1990.

.2. Chelation therapy

We considered as having received chelation therapy (CT) patients who werereated for at least 6 months (in fact, no patient had received CT for a shorter period).

e arbitrarily considered as “adequate” iron CT the use of deferoxamine (DF0) sub-utaneously (40 mg/kg/d, in slow infusion over 8–12 h, for at least 3 days per week),

rch 34 (2010) 864–870 865

2.3. Outcome and statistical analysis

Assessment of the effect of CT on survival was made in the 97 patients with lowand int 1 IPSS. Numerical variables were summarized by their median and quartilesor range; categorical variables, by counts and relative frequencies. The primary endpoint was overall survival (OS) defined as the time between diagnosis and death(from any cause) or last follow-up (censored observations). Actuarial probabilityof OS was estimated using the Kaplan–Meier product limit method, and compar-isons between the Kaplan–Meier curves made by the Log-Rank test. Data werecensored at the end of follow-up (November 15th, 2007). Univariate descriptiveanalysis and multivariate analysis (Cox proportional hazards regression) were per-formed to identify the most significant independent prognostic factors affecting OS.After assessment of the proportional hazard assumption, all parameters that wereunbalanced between the two groups (chelated or not), were included in the Coxmodel. All analyses were performed using SAS package version 9.01 (SAS Institute,Cary, NC).

3. Results

3.1. Characteristics of the patient population at inclusion

170 patients from 18 centers (10 University hospitals and 8transfusion centers) were included between 15th May and 15thJune, 2005, of whom 165 could be reanalyzed at the reference dateof 15th November 2007 (the remaining 5 were lost to follow-up).Karyotype had been successfully performed in 117 of those 165patients, 97 of whom had low or int 1 IPSS and are the subject of thepresent work. Seventy of those patients were classifiable using theWPSS, while the remaining 27 had been classified by FAB criteriaonly, and data on multilineage dysplasia was lacking.

All 97 patients were transfused as outpatients. Their baselinecharacteristics are shown in Table 1. Sixty-nine of them had co-morbidities (ranging from 1 to 5 co-morbidities per patient, mean1.7). In 44 patients (45.4%) co-morbidities were all considered non-iron related, while in the remaining 25 patients (25.8%) at least oneof the co-morbidities was considered as possibly iron related. Co-morbidities potentially associated with iron overload were cardiacdisorders (non-ischemic cardiomyopathy and cardiac arrythmias)in 24 cases, diabetes mellitus in 8 cases and liver cirrhosis in 1case. Mean serum ferritin (SF) level was 541 ng/ml (range 33–2059),1491 ng/ml (range 436–6572) and 2788 ng/ml (range 16–12,460) atdiagnosis, onset of CT and last evaluation, respectively.

Forty-four (45%) of the 97 patients had received no CT while53 pts (55%) had received CT for at least 6 months. CT had startedprior to inclusion in 48 of them, and after inclusion in the 5 remain-ing patients. Median interval from diagnosis to onset of CT was23 months (range 3–192). CT received is listed in Table 2. Medianduration of CT was 36 months (range 6–113+). As seen in Table 1,non-chelated patients were significantly older (mean 75 versus70, p = 0.047) and had higher IPSS (mean 0.5 versus 0.4, p = 0.02)than chelated patients, while there were no significant differencesin WHO classification (p = 0.13) and WPSS (p = 0.32). Twenty-two(50%) of the non-chelated and 36 (67%) of the chelated patientshad received erythropoiesis stimulating agent (ESA) for at least 6months (p = 0.11), while 1 non-chelated and 8 chelated patientsreceived thalidomide (p < 0.002), with no or transient effect, even-tually resulting in RBC transfusion requirement. No patient hadreceived other treatments potentially active on MDS, such aschemotherapy, hypomethylating agents, antithymocyte globulin orlenalidomide.

The cumulative number of PRBC received at the end of thestudy was higher in chelated than in non-chelated patients (mean192 versus 123 respectively) (p = 0.001) but monthly transfusion

866 C. Rose et al. / Leukemia Research 34 (2010) 864–870

Table 1Patient characteristics and outcome.

All patients (n = 97) Non-chelated patients (n = 44) Chelated patients (n = 53) P-value

Mean age, years 72 75 70 0.047Gender, n (%) 0.57

Male 55 (59.7) 26 (59.1) 29 (54.7)Female 42 (43.3) 18 (40.9) 24 (45.3)

WHO classification, n (%) 0.13Missinga 15 6 95q-syndrome 8 (9.8) 2 (5.3) 6 (13.6)RAEB1 20 (24.4) 11 (28.9) 9 (20.5)RA 10 (12.2) 4 (10.5) 6 (13.6)RARS 23 (28.0) 9 (23.7) 14 (31.8)RCMD 4 (4.9) 3 (7.9) 1 (2.3)RCMD-RS 5 (6.1) 1 (2.6) 4 (9.1)Unclassified 12 (14.6) 8 (21.1) 4 (9.1)

IPSS, n (%) 0.044Low (0) 45 (46.4) 15 (34.1) 30 (56.6)Int 1 (0.5–1) 52 (53.6) 29 (65.9) 23 (43.4)Mean 0.4(0.4) 0.5 (0.4) 0.3 (0.4)

WPSS, n (%) 0.33Patients assessed 70 30 401–<3 37 14 (46.7) 23 (57.5)

≥3 33 16 (53.3) 17 (42.5)Mean total number of PRBC transfused (range) 160 (6–953) 123 (6–953) 192 (28–448) <0.001

Transfusion requirement, (mean PRBC/month)Since diagnosis 2.7 2.6 2.8 0.52Since onset of transfusions 2.9 2.8 3.1 0.76

Latest mean serum ferritin value, ng/mlb 2788 2786 2790 0.86Mean number of co-morbidities 1.7 1.8 1.6 0.46

Patients with non-iron-related co-morbidities, n (%) 44 (45.4) 24 (54.5) 20 (37.7)Patients with possibly iron-related co-morbidities, n (%) 25 (25.8) 9 (20.5) 16 (30.2) 0.27

Leukemic transformation 0.087No 73 29 44Yes 24 15 9

Number of deaths 66 39 27 0.514c

Causes of deathCardiac 20 (30.3) 10 (34.5) 10 (37.0)Hepatic 1 (1.5) 1 (2.6) 0Infection 13 (19.7) 6 (15.4) 7 (25.9)Other cancer 3 (4.5) 2 (5.1) 1 (3.7)Bleeding 4 (6.1) 3 (7.7) 1 (3.7)AML 23 (34.8) 15 (38.5) 8 (29.6) 0.78Unknown 2 (3.0) 2 (5.1) 0

a But classified according to FAB (RA n = 9; RARS n = 4; RAEB n = 1).b s in c

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Median interval between last ferritin assessment and end of study was 4 monthc Distribution of causes of deaths.

atients with iron related co-morbidities (9 of 44, 20.5%, in non-helated group versus 16/53, 30.18% in chelated group) (p = 0.27)nd in serum ferritin level at last available analysis (p = 0.86). How-ver, the median interval from last ferritin level to the end of studyas 4 months (range 1–6) in the chelated group compared to 14

able 2ron chelation therapy in 97 low-risk patients with MDS.

Patients, n

No chelation therapy 44Chelation therapy 53Adequate chelation 41Deferoxamine s.c. continuous (8 h, 40 mg/kg/day)a 28Deferiprone (30–75 mg/kg/day) 5Deferiprone + Deferoxamine s.c. 4Deferasirox (20–30 mg/kg/day) 4Weak chelation 12Deferoxamine i.v. (50–100 mg/kg)b 5Deferoxamine s.c. bolus (2–3 g/week) 7

a At least 3 days/week.b Once daily following red blood cell transfusion.

helated patients (range 1–6) and 14 months in non-chelated (range 1–38).

months (range 1–30) in non-chelated patients in whom ferritinlevel monitoring was less frequent.

In one patient with RARS, who had received RBC transfusionsfor one year (3 PRBC every month), the transfusion requirementslightly decreased to 2 PRBC every 2 months, 6 months after theonset of chelation, without any other explanation than CT itself. Noimprovement in anemia or other cytopenias was reported on CT inany other patient.

3.2. Outcome of chelated and non-chelated patients

During the study, progression to AML occurred in 15/44 (34%)of non-chelated and 9/53 (17%) of chelated pts (p = 0.087) and 66 ofthe 97 patients died, including 27 (27.8%) and 39 (40.2%) of chelatedand non-chelated patients, respectively. Median overall survival

C. Rose et al. / Leukemia Research 34 (2010) 864–870 867

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Table 3Cox model analysis on survival.

Parametera Chi2 P-value Hazard ratio 95%CI

Adequate chelation 12.92 0.0003 0.302 0.16–0.58Transfusion requirement >3

PRBC/month8.91 0.0028 2.516 1.37–4.61

ig. 1. (a) Survival in chelated versus non-chelated patients with IPSS low and Int-risk MDS, (b) survival in MDS patients according to the intensity of chelationherapy.

median 124 months) than weak chelation (median 85 months< 0.001) (Fig. 1b).

Due to differences in some recognized prognostic factorsetween chelated and non-chelated patients at inclusion, theurvival analysis was repeated after adjustment for known prog-ostic parameters in MDS, including age, IPSS and transfusionequirement. Using this analysis, the survival difference remainedignificant between chelated and non-chelated patients. In par-icular, in IPSS low patients, median survival was 138 monthsn chelated patients versus 70 months in non-chelated patientsp = 0.015) (Fig. 2a), while in IPSS int 1, median survival was 115

onths in chelated patients versus 36 months in non-chelatedatients (p = 0.003) (Fig. 2b). In patients who received less thanPRBC per month, median survival was 124 in chelated patients

ersus 77 in non-chelated patients (p = 0.03) (Fig. 3a), while inatients who received 3 or more PRBC/month median survivalas 138 months in chelated patients versus 28 months in non-

helated patients (p < 0.0001) (Fig. 3b). In patients aged less than7, median survival was not reached in those who received CTersus 36 months in those who were non-chelated (p < 0.0001),hile in patients older than 77 median survival was 124 months

n those who received CT versus 77 months in those who receivedo CT (p = 0.04). Therefore, survival differences between chelated

Fig. 2. Survival in chelated versus non-chelated patients with (a) low-risk MDS and(b) Int-1-risk MDS.

ment (from onset of transfusions) (p = 0.0001), age (p = 0.03), andnumber of co-morbidities (p = 0.02).

Parameters that showed significance in univariate analysis andthose that differed between the 2 groups (including age, numberof co-morbidities and IPSS) were included in a multivariate Coxanalysis, along with chelation and its intensity (adequate versusweak) as dependent covariates. Adequate chelation was found tosignificantly improve overall survival in an independent manner(HR 0.302; p = 0.0003; CI 0.16–0.58). The other independent prog-nostic factors for survival were IPSS and transfusion requirement(Table 3).

A similar multivariate analysis was done using WPSS insteadof IPSS in the model; adequate chelation was also found to sig-nificantly improve overall survival in an independent manner (HR

IPSS >0 4.13 0.0420 1.929 1.02–3.63Age >72 years 1.64 0.2004 0.678 0.37–1.23Co-morbidities >3 0.40 0.527 1.288 0.59–2.83

a Global test (Wald) p = 0.00003.

868 C. Rose et al. / Leukemia Resea

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ig. 3. Survival in chelated versus non-chelated MDS patients with (a) transfusionequirements <3 PRBC/month and (b) transfusion requirements >3 PRBC/month.

. Discussion

In this heavily transfused cohort of low and int 1 risk MDS,significant survival advantage was seen in chelated patients,

articularly in those who had received sufficiently intensive chela-ion therapy. This survival advantage persisted after adjustmentor known prognostic factors in MDS, including IPSS, age, WPSS,evel of transfusion requirement and number of co-morbidities, and

as more important in heavily transfused and younger patients.urthermore, adequate chelation therapy emerged, in a mul-ivariate Cox analysis, as a powerful prognostic parameter forurvival.

So far, a survival advantage with iron chelation in heavilyransfused MDS had been suggested in only one relatively smalletrospective study [30] where patients with low or intermediate-IPSS risk who had received CT had a median survival that was

ot reached at 160 months compared to 40 months in patientsho had received no CT [25]. However, this study compared

nly 18 chelated patients to 160 non-chelated patients from annitial series of 178 patients and did not take into account co-

orbidities, previous treatments, WPSS score, while the medianuration of chelation therapy was short (15 months) [25]. Anotheretrospective survey in transfusion-dependent MDS and aplasticnemia also suggested a negative impact of iron overload and a

A possible bias, in our work, was that although patients wererospectively followed up over 2.5 years after inclusion, the deci-

rch 34 (2010) 864–870

sion to administer or not CT was not randomized. Therefore,clinicians could presumably have administered CT to patientswhom they believed had a better prognosis. Indeed, non-chelatedpatients were older (mean 75 versus 70) and had a somewhathigher IPSS (mean 0.5 versus 0.4). On the other hand, the sur-vival advantage, in chelated patients, was found both in IPSS lowand int 1 patients, both in heavily (>3 units/month) and somewhatless transfused (<3 units/month) patients, and irrespective of age.Furthermore, adequate iron CT therapy emerged in multivariateanalysis as a powerful prognostic factor of survival. Another issueis that we failed to identify significant increases in specific causesof death in non-chelated patients that would have helped under-stand how CT possibly improved survival. There was in particularno excess of deaths possibly attributable to iron overload (in par-ticular of cardiac, endocrine or liver origin). On the other hand,there was a trend with a higher incidence of AML progression inthe non-chelated group. Recently, a large Spanish study, so far pre-sented only at international meetings, suggested that iron overload(serum ferritin above 1000 ng/mL) was independently associated toa higher incidence of AML progression [32]. Pullarkart also recentlysuggested that CT possibly improved survival in MDS by reducingthe risk of progression to AML [33]. It has been indeed suggestedthat iron overload could be involved in carcinogenesis by activationof oxidative responsive transcriptions factors and pro inflammatorycytokines, iron-induced hypoxia signalling [34] and production ofreactive oxygen species and free radicals [34]. In addition, ironchelators have demonstrated an anti-proliferative activity in vari-ous cell lines [35] including myeloid cell lines [36] and could havean anti-neoplastic activity [37,38]. Regarding other causes of deathsin chelated and non-chelated MDS, while Pullarkat suggested thatCT could also potentially improve survival in MDS by reducing theinfectious risk related to iron overload, we found a similar incidenceof infectious deaths in chelated and non-chelated patients. How-ever, the beneficial effect of CT on infections may be more importantwith deferasirox than with desferoxamine (the most widely usedagent in our patients), as iron-bound deferoxamine can act as asiderophore potentially promoting the growth of pathogenic fungi[39].

The observation that iron chelation therapy was associated withlonger survival without a significant differences in specific causesof deaths, compared to non-chelated patients, could also be dueto the possibility that iron overload was only a cofactor of mor-tality in this elderly population. Our cohort was indeed older onaverage than most previously published series of MDS patients[3] and patients generally had one or more co-morbidities. Ironmay be more toxic in older patients with several co-morbidities,while iron toxicity may be more difficult to demonstrate in thosepatients, each co-morbidity constituting a potential cause of death.This stresses the value of prospective studies assessing more pre-cisely the potentially deleterious effect of iron overload in differentorgans, especially in the heart where cardiac MRI data have beenso far conflicting [40–44].

Finally, a survival advantage in chelated patients could resultfrom a positive role of chelation therapy on hematopoiesis, sug-gested in a previous report [45]. However, except in one case, weobserved no significant and durable improvement of cytopenias,in spite of the long median duration of chelation therapy. Alsoof note is that the last serum ferritin levels available were sim-ilar in chelated and non-chelated patients, although one wouldhave expected higher serum ferritin levels in non-chelated patients.On the other hand, serum ferritin was less often measured in the

In conclusion, in spite of potential biases as the study was notrandomized, our results in this heavily transfused low and int 1 risk

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DS cohort suggest that chelation therapy could improve survival.rospective randomized studies will be required to confirm thisffect, and precisely analyse reasons for this survival advantage, ifonfirmed.

onflict of interest

None.

cknowledgements

We thank Ph Richardot who performed independent statisti-al analysis and all Participants centers: Service d’hématologie,HU Cochin, Paris, D. Vassilief; F Dreyfus. Service d’hématologie,HU Avicenne, Bobigny, P. Fenaux, S Brechigniac. Service d’onco-ématologie, CH Saint Vincent de Paul, C. Rose, M Wemeau. Service’hématologie, Centre H. Becquerel, Rouen, A. Stamatoullas. Ser-ice d’hématologie, CHU Brabois, Nancy, A. Guerci-Bresler. Service’hématologie, CHRU, Limoges, D Bordessoulle, D Chaury. EFS, Pon-oise, D. Larbaa. Service d’hématologie, CHU Purpan, Toulouse,. Beyne-Rauzy. EFS, Perpignan, Docteur L. Dumazert. Service’hématologie, CHU Hôpital Jean Bernard, Poitiers, L. Roy. Ser-ice d’hématologie, CHU Clémenceau, Caen, S. Cheze. Service’hématologie, CHU Hôtel Dieu, Nantes, B. Mahe. EFS Rhône-Alpes,nnecy, B Laubriat. EFS, Bordeaux, A. M. Ferrer. EFS Auvergne-Loire,aint Etienne, D. Goure. EFS Rhône-Alpes, Valence, F. Bernard. EFS,aval, M. C Bauvin. EFS Rhône-Alpes, Annemasse, P. Boutou.

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